Aging significantly dysregulates the immune system affecting both composition and function of immune cells. However, mechanism of this process remains poorly understood. Here, to understand this process we characterized B cells in aging hosts, as their impairment not only increases risk of serious complications from seasonal infections in the elderly, but also renders vaccines ineffective in reduction of flu-related deaths and hospitalizations. We previously reported that this problem can be circumvented by modifying a vaccine formulation (Olkhanud et al, Vaccine, 2011). For example, our Alzheimer's disease (AD) vaccine formulation, termed Abeta-CoreS, induces a potent humoral response and alleviates AD even if used at the onset of the disease in old mice when traditional vaccines are ineffective. We recently found that aged humans, primates and mice accumulate a novel type of activated B cells. These cells termed 4BL cells induce the generation of granzyme B (GrB) and perforin CD8+T cells (Lee-Chang et al., Blood, 2014). We also reported that 4BL cells are derived from innate B1a cells that produce natural antibody (Lee-Chang et al., 2016). Contrary to widely believed assumption that innate B cells do not change upon aging, we showed that the aging renders them to lose their immune suppressive function and to become superb inducers of cytolytic T cells. We also found that this conversion is induced by aging human monocytes and murine peritoneal macrophages. By utilizing 4-1BB and CD40L, elderly human and murine myeloid cells convert young host B1a cells to upregulate 4-1BBL, IFNR1, CD86 and membrane TNF. This enables activated B1a cells (4BL cells) to induce expression of granzyme B in CD8+T cells by targeting TNFR2 via mTNF while providing co-stimulation with CD86. We now report that 4BL cells are responsible for the increased hyperglycemia, insulin resistance (IR) in aged hosts. Using healthy aged mice and macaques, we report that IR is induced by activated innate 4-1BBL+ B1a cells (a.k.a. 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. Mechanistically, loss of Akkermansia muciniphila impairs the intestinal integrity causing leakage of bacterial products such as endotoxin to activate CCR2+ monocytes (MO) when butyrate is decreased. Upon infiltration in the omentum, CCR2+ MO convert B1a cells into 4BL cells which then induce IR via 4-1BBL. This pathway and IR are reversible, as supplementation with A. muciniphila alone or enrofloxacin, which increases its abundance, restores normal insulin response in aged mice and macaques. Additionally, treatment with butyrate or antibodies that eliminate CCR2+ MO or 4BL cells have the same effect on IR. These results underscore the previously unknown pathological function of B1a cells, suggesting that the microbiome-MO-4BL cell axis can be targeted to reverse IR and possibly other age-associated pathologies. Overall, the project is progressing well as planned. It continues generating novel insights with significant scientific and clinical implications.
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